The long-term goals of this project are to understand the mechanisms, role and significance of electrical control of insulin secretion and development of diabetes. Much previous work has demonstrated the central role of the K-ATP channel in electrical activity of the pancreatic ?-cell and has revealed how defective K-ATP channel activity can have profound effects on insulin secretion and cause neonatal diabetes. This has led to transfer of these patients from insulin to sulfonylurea therapy, with marked improvements in lifestyle and disease outcome. Based on new preliminary data, we propose that failure of insulin secretion due to altered electrical activity may be more prominent than previously realized, and that multiple unrecognized molecular components are likely to be relevant to excitation-secretion control and the development of diabetes. To pursue these ideas, we will utilize unique animal models to assess quantitative relationships between islet K-ATP activity and insulin secretory control, and we will utilize innovative forward genetic approaches in model organisms to search for novel regulators of metabolism-excitation coupling. In the process, the proposed experiments will test mechanistic hypotheses regarding metabolism-excitation-secretion coupling in islets and in the etiology of different forms of diabetes and will provide mechanistic information that will impact treatment approaches.